The characteristics of aerosol inhalation patterns for deposition in the respiratory tract, as well as their clearance from the respiratory tract, have been well documented (Yeates, D. B. and Mortensen J. Deposition and Clearance, In: Murray J F. Nadel J A: Textbook of Respiratory Medicine, et 3.Philadelphia, WB Saunders Company, Vol. 1. Chapter 15 pp. 349-384, 2000).
Reduction in Aerosol Inhalation Times
Aerosol drug therapies from liquid solutions, liquid suspensions, and dry powder suspensions have been used in hospitals, outpatient clinics, and at home. Of the new drugs being developed, it has been estimated that 16% will be delivered via the respiratory tract. This includes the treatment of both respiratory and non-respiratory diseases. These new agents include antibiotics, anticancer agents, surfactants, hormones, proteins and peptides. Whereas there are excellent nebulizers for the delivery of microgram quantities of many small molecules, efficient and effective aerosol delivery of many of the above agents presents new challenges for aerosol delivery systems. A result of the limitations of current technology is that, in order to provide a therapeutic level of drug to the pulmonary system, an extended time period for inhalation is required. The necessity, in some cases, to deliver milligram masses to the lungs rather than microgram masses has led to inhalation treatment times of up to 2-3 hours per day. This is to the detriment of patient comfort and, possibly, compliance. For instance, the Respimat™ metered-dose inhaler, is a small device in which two pressurized liquid jets collide to produce a fine aerosol with 11-15 μl being dispensed at each actuation (breath). However, it will only nebulize liquids, not suspensions. The dose per breath is very limited and the aerosol will readily change in size due to evaporation. There are numerous jet-type nebulizers available with perhaps the ePARI, PARI LC Star™ and the Aerotech II™ representing the best of these. These nebulizers have fluid flow rates of up to 0.89, 0.62 ml/min and 0.39 ml/min, respectively, with the PARI LC and Aerotech II™ respectively, having 80% and 77%, particles being less than 5 μm in diameter. Typically, jet type nebulizers produce aerosols with geometric standard deviations of about 1.8-2.3. The polydispersity does not make them ideal for the delivery of drugs to the lower respiratory tract; however they are relatively inexpensive. The markedly higher dose rate (4-5 ml/min) provided by the use of an aerosol processing and inhalation system, APIS will result in reduced treatment times.
Reduction in Shear Degradation
Some polymeric molecules and biologics are sensitive to shear degradation and consequent loss of desired activity. Shear degradation can be minimized by the generation of droplets which are too large to penetrate into the respiratory tract.
Delivery of Sparsely Soluble Agents
Some agents are sparsely soluble. In these cases, both large volumes of fluid and long inhalation times are required to deliver an effective dose of the active agent. The controlling (critical) parameters are a) the liquid flow rate b) the total input of unsaturated air and c) the output particle size. The initial size of the aqueous/solvent-based aerosol generated is dependent on the mass of the agent in solution or suspension such that on complete evaporation of the solvent, the residual particles have aerodynamic diameters between 1 and 7 μm. For example, a sparsely soluble compound will require the generation of very large droplets whereas very soluble compounds such as NaCl or sugar require the generation of smaller droplets. To optimize the rate of drug delivery the aqueous solvent flow rate should be 1-5 ml/min. Thus, aerosol generators should be chosen to generate the optimal size droplets such that on evaporation a solid phase aerosol of the desired respirable size, typically between 1 and 7 μm aerodynamic diameter results.
Alternate Method for the Generation and Delivery of Dry Powder Aerosols
Suspension of powders to form respiratory aerosols is difficult and sometimes impractical due to the surface forces between the molecules and agglomeration of the composite particles. Excipients are used to help facilitate aerosolization but these reduce the drug load per particle. Dry powder inhalers can require relatively rapid inhalation rates of 1 l/sec to disperse the powder, resulting in bronchial rather than deep lung aerosol deposition. Due to formulation issues, the drug and the inhaler are often designed to work together. There are several hand held devices available, including Rotahaler™ Turbuhaler™ and Diskhaler™. The Nektar™ dry power inhaler uses an independent power source to disperse the powder from a “blister”. The powder contains drug particles (<5 μm MMAD), lactose or glucose particles (>30 μm diameter) or micronized particles. Typical doses delivered range from 4 to 450 μg with the Nektar product, providing 2-5 mg of solids per puff.
Compact Design
Large devices have obvious disadvantages in use. For example, an evaporator/concentrator previously described, (Pillai, R. S., Yeates, D. B., Eljamal, M., Miller, I. F. and Hickey, A. J. Generation of Concentrated Aerosols for Inhalation Studies. J. Aerosol Sci., 25(1):187-197, 1994.) had a volume of 200 l and was 5 ft long and 1 ft in diameter.
Inhalation Regulated Aerosol Delivery-Respiratory Aerosol Control System, RACS
Manually operated and breath-activated metered dose inhalers are the most commonly used devices for aerosol administration of medications. In a manual metered dose inhaler the drug delivery is manually activated by the patient. This requires the patient to have good coordination skill to operate these devices for efficient drug delivery. It is estimated that more than half of patients are unable to use the device properly and efficiently. Major problems with a manual metered dose inhaler include timing coordination between activation of drug delivery and inspiration of aerosol medication, multiple activation of drug delivery during inspiration, improper breath-holding, and operation difficulty with insufficient hand strength (young child, elderly or seriously ill). Another problem with metered dose inhalers and dry powder inhalers is that the inspiratory effort required to activate drug release results in a high inspiratory flow that causes excess aerosol deposition in the oral cavity and larynx. All these limitations make these manual metered dose inhalers sub-optimal for delivering aerosol medication.
Delivery of aerosolized agents has generally been limited to a given mass of fluid that is aerosolized at the beginning of each breath. When the mass aerosolized is independent of the size and depth of breathing, optimal use of the patient's breathing pattern is not utilized to achieve maximal delivery of the drug. Some devices are either operator-activated or activated by the flow caused by the initiation of the breath. In these devices a set dose is delivered independent of the size of the breath. In many situations the drug solution is placed in the reservoir of a nebulizer and the patient is instructed to inhale the medication until the medication has been completely aerosolized. The mass of drug leaving the nebulizer and that deposited within the desired region of the respiratory tract can vary greatly depending on the technique. These methods do not provide a dose which is dependent on breath volume. The inhaled volume is, in part, determined by the size of the patient.
To provide a better inhaler for aerosol delivery of medication, a variety of delivery systems and methods have been attempted and are the subject of U.S. patents. The major focus of these patents has been the provision of a breath-activated apparatus for the timing of the actuation of a metered dose inhaler, MDI and the assessment of inspiratory flow using a) measurements of the pressure drop across a resistive element b) a Venturi flow meter or c) the negative pressure caused by an inspiration. This signal has been used to regulate the valve on an MDI and provide flow and volume information to the user. These patents include:
Nichols, et al (U.S. Pat. No. 6,491,233; U.S. Pat. No. 6,854,461) discloses an aerosol generator and breath-activated methods of delivering an aerosol, in which the aerosol is generated by heating a medicated fluid as it flows through a capillary tube. It utilizes a pressure drop to trigger delivery of a given dose of the aerosolized agent at the beginning of a breath. Once the pressure drop is detected, the aerosol can be delivered to the user. However, this system and method makes no provision for concentrating the generated aerosol particles, as does the present invention. It also makes no provision for an outlet for the patient's exhalation and a constant air supply, so that the patient must disconnect his/her mouth from the mouthpiece for the next inhalation. It is unsuitable for operation as a respiratory control delivery device in conjunction with APIS which has a constant air supply flowing through the concentrator and a positive pressure at the output.
Cox, et al (U.S. Pat. No. 6,516,796; U.S. Pat. No. 6,557,552) discloses an aerosol generator and methods for using it. The generator comprises a heated flow passage, a source of material to be volatilized, a valve to regulate material flow, and a pressurization arrangement to cause material to flow. However, this method makes no provision for concentrating the generated aerosol, as does the present invention.
Poole (U.S. Pat. No. 6,158,431) discloses a portable system and method for delivering therapeutic material to the pulmonary system, comprising a droplet dispersion chamber, a droplet generating assembly, an assembly for heating and evaporating the droplets, and a delivery system. However, this system and method makes no provision for producing monodisperse aerosol particles in the optimum 1-7 μm diameter size range, nor does it make any provision for concentrating the generated aerosol particles, as does the present invention.
Lloyd et al. (U.S. Pat. No. 5,469,750) and Goodman et al. (U.S. Pat. No. 5,813,397) disclose a breath-activated microcontroller-based apparatus for delivery of aerosol medication for inspiration from a metered dose. However, this apparatus makes no provision for providing an outlet for the patients' exhalation and a constant air supply flowing (such that patients have to disconnect their mouth from the mouth piece for the next inhalation). The present invention enables continuous breathing without the necessity to disconnect from the device.
In all of the above-reported systems, the primary focus has been the development of hand-held devices which deliver doses of up to a few micrograms of active drug per breath. None of the systems and methods described in U.S. patents or in the literature for commercially available products deliver aqueous-based respirable aerosols at high dose rates of over a milligram of active agent per breath as a qeometically stable solid phase aerosol. The technology and methods that are the subject of this invention are particularly suitable for delivery of aqueous-based aerosols containing large molecules, genetic material and other therapeutic agents to the pulmonary system.
Thus, there is a need for a new aerosol processing and inhalation system that is suitable for delivery of aqueous-based aerosols containing large molecules, genetic materials and other therapeutic agents to the pulmonary system at a high dose rate, and in a manner that is both therapeutically effective and comfortable for the patient. The present invention provides a method and system for generating 10-30 μm aqueous or nonaqueous droplets, evaporating solvent from the droplets, and concentrating the aerosols to produce 1-7 μm aerodynamic diameter dry particles. By removing most of the carrier air and the unwanted vapor, respirable aerosols are delivered at a high dose rate.